Conventional drug administration methods entail periodic dosing of a therapeutic agent in a formulation that ensures drug stability, activity, and bioavailability. These methods of administration include parenteral delivery such as by injection, topical delivery using salves or ointments for skin applications or via liquid drops for eye and ear applications, and oral delivery by ingestion, for example of pills, tablets or liquids. Administration of these drug dosage forms results typically in a sharp initial increase in drug concentration, followed by a steady decline in concentration as the drug is cleared and/or metabolised. Repeated administration is necessary, to reach and maintain the drug concentration within the appropriate efficacy range. The result of this periodic drug delivery is a drug concentration profile that oscillates over time.
For drugs that are unstable in the blood stream or gastrointestinal tract, are toxic at high doses or have a narrow therapeutically effective concentration range (therapeutic window), conventional drug delivery methods are inappropriate. Recently developed protein drugs, for example, present unique challenges for drug delivery. Because of their protein nature, oral administration results in protein digestion or hydrolysis in the gastrointestinal tract. Proteins also have very short pharmacokinetic half-lives in the blood stream, being quickly metabolized and cleared, which renders parenteral administration inappropriate. Also, because of their size, proteins are poorly absorbed through the skin and so cannot readily be delivered by topical administration.
To provide for the delivery of such macromolecular drugs, and particularly protein drugs, alternatives to the traditional delivery methods have been explored. One promising approach entails the use of biocompatible, non-degradable polymers as drug delivery vehicle. In this approach, the drug is dispersed within a polymeric matrix that is wettable, i.e., capable of imbibing water, and which serves to control the rate at which drug is released. Use of these polymeric delivery vehicles offers several advantages over conventional modes of drug administration. Polymeric systems can be localized to the desired target site, for example by topical application, by implantation, or by ingestion, to reduce systemic toxicity and increase drug potency. Because of the controlled rate at which these polymeric vehicles release drug, plasma drug concentrations can be maintained within an appropriate therapeutic window, and harmful side effects reduced. Also, the discomfort associated with multiple injection therapy can be eliminated, thus improving patient compliance.
A variety of polymer-based drug delivery systems have been developed, which differ largely in the mechanism by which release of the drug from the matrix is achieved. For low molecular weight drugs that are soluble in polymer, for example, release from the matrix can occur by diffusion, with the drug dissolving in water imbibed by the matrix and then diffusing down the chemical gradient to the polymer surface. Release by dissolution/diffusion has been demonstrated in polymers such as silicone rubber, polyethylene and nylon film, for such drugs as testosterone, phenobarbital, progesterone and caffeine.
The large size of macromolecular compounds, such as peptide and protein drugs, was thought to be prohibitive to diffusion from the polymeric matrix. Prolonged release of proteins in the size range from 14 kD to 250 kD was achieved, but at poorly controlled rates, by loading into a matrix of polyethylene-vinyl acetate (EVA), polyhydroxyethyl methacrylate or polyvinylalcohol (see Langer et al, Nature, 1976, 263:797; and see Langer et al, U.S. Pat. No. 4,391,797 issued Jul. 5, 1983). Studies of the protein release kinetics indicated that proteins were released from the matrix by first dissolving in matrix-imbibed water, leaving voids in the matrix which when invaded by water caused the dissolution of neighbouring protein molecules, thereby creating a network of pores leading to the matrix surface. Prolonged release appeared therefore to arise from the tortuous paths generated by the dissolution/diffusion process.
A drawback of delivery devices that employ a diffusion-based release mechanism is that drug release is time-dependent, that is, a constant amount of drug is not delivered over the life of the device. As with conventional modes of drug administration, drug release follows first order kinetics, and an initial sharp increase in drug concentration is followed by a drug concentration that declines gradually as the matrix-loaded drug dissolves. Moreover, the porous network required for diffusional release of the drug to the external environment can be established only by high volumetric loading of drug in the matrix, which raises concerns for toxicity and adverse side effects, and is particularly inappropriate for proteins and other drugs that require low dosages, and have a narrow therapeutic window, i.e., the difference between the lethal dose (LD.sub.50) and the effective dose (ED.sub.50) of a given drug.
An alternative to the mechanism of drug release by diffusion from polymers, and one which offers drug release at a prolonged and constant rate, is that of osmotic rupturing, which relies on osmotic pressure as the driving force for drug release. In this approach, osmotically active drugs or drug salts are dispersed as discrete particles within a wettable, polymeric matrix, typically polyethylene-vinyl acetate copolymer or polydimethylsiloxane. In response to water imbibed by the matrix, particles encapsulated therein swell as osmotic pressure builds until the tensile strength of the elastomer is overcome, and eventually ruptures, releasing the drug particles which further dissolve in the aqueous environment. Serial rupturing in this manner generates a porous network, allowing water to migrate further within the matrix, thereby causing further rupturing and drug particle release.
Drug delivery systems employing the osmotic rupturing mechanism of drug release are particularly attractive because they offer sustained and relatively constant drug release profiles. However, as with systems based on the diffusion mechanism of drug release, the osmotic rupturing mechanism requires relatively high volumetric loading of the polymer, to establish the porous network required to sustain rupturing and drug release. This makes low dose delivery of drugs problematic when osmotic rupturing type delivery devices are contemplated.
It is an object of the present invention to provide a polymer-based delivery system which is adapted to release a selected drug in low dose levels and in a sustained and controlled release fashion.
It is another object of the present invention to provide a polymer-based delivery system which is adapted for use generically to release a therapeutic macromolecule at low dose levels and in a sustained and controlled release fashion.
It is another object of the present invention to provide a method for delivering a therapeutic macromolecule to a patient in low dose levels at a sustained and relatively constant rate.
It is another object of the present invention to provide a process for preparing a polymer-based system which is useful to release a selected therapeutic macromolecule in low dose levels at a sustained and relatively constant rate.